Sunday, February 19, 2017

Florence in the thirteenth through the sixteenth centuries
was fraught with battles between factions. Primarily the Guelphs and Ghibellines.
The Guelphs support the Pope, who himself went from Rome to Avignon and
eventually back again, and the Ghibellines who supported the Imperial forces
from the Holy Roman Empire. Family killed off family. It led to even more internecine
war between Black Guelphs and White Guelphs.

Expelled from Florence were the likes of Dante and Petrarch.
Ending with the Medici and their own form of butchery, including if one likes
the famous St Bartholomew's Day Massacre of Huguenots in Paris, under the
influence of the Medici French Queen mother. One can best understand this Massacre
by reading Dumas, his brilliant work on this event.

Thus, Civil Wars are not as simple as our own between North
and South. It can occur between the first floor and the second floor. It can
start over what Pope is best or whether one likes Germans or French, Pope or
Emperor.

Yemen has gone through a rather long rough patch, to say the least. Around the time of the Prophet the port city of Aden change control from Ethiopians, Jews, Persians, Arabs, and before that Romans. So one would assume Yemeni folk would have some sense of this ongoing turbulence.

But we now have what seems to be the "snowflake" syndrome. Namely, despite millennia of conflict the current generation abhors any sense of unease. The most recent is the use of Science, as well as Nature, as vehicles of complaining. Perhaps on the Nature side we have the left in England, and on the Science side we have a former Democrat politician at its head.

It may be useful to get politicians out of everything. Otherwise we may find ourselves in a blizzard of snowflakes.

In the recent book by Fuller,The Book That Changed America: How Darwin's Theory of Evolution Ignited a Nation, the author claims to present how the introduction of Darwin's work transformed the United States. I would beg to differ. Perhaps a better title would have been, "The Book that
Changed Concord and Cambridge" because it clearly focused on the group
from Concord along with a smattering from Cambridge.

The author starts out with
the recognition of Boast as the "Hub" at this period as compared to
New York, albeit bigger, yet a more raucous version of an American city. Boston
reached back to European intellectual elitism whereas New York was starting to
become an eclectic American melting pot. Boston sought comfort in lineage,
whereas New York had quickly abandoned its Dutch heritage, predating the
Pilgrims, and was decade by decade introducing one culture after another, with
the conflicts, but working towards an amalgam.

Concord was at this time literally a train ride, at that
time, from Boston, Cambridge a collection of people, high and lower class,
factories and Harvard. Harvard was founded as many Bostonian may recall as a
place to send the graduates from Boston Latin School, the educational
establishment for the local "well-off". Back in Concord were fields
for modest farms as well as a small collection of educated folks who founded
such places as Concord Academy, aside the Concord River and just on the
outskirts of then the center of Concord. Along the adjoin streets were gracious
homes of those who constituted the general Concord society.

Along comes Darwin into this Transcendental soup of Thoreau,
Alcott, Emerson and others and in a strange way the fact based scientific
observations of Darwin and his line of reasoning leading to evolution gets
absorbed by this group who have to then eschewed this very approach to
understanding. Thus sayeth the author.

At first the author introduces Gray and Agassiz.Gray the botanist, and Agassiz the broadly
based naturalist. Gray comes across as the mild manner scientists who sees in
Darwin a way to explain many of the observations concerning nature he has made
in plants. Gray is subdued, and academic. Then there is Agassiz, the Swiss
naturalist, with an ebullient personality, who sees in Darwin the conflicts
with his fundamental religious beliefs. Gray sees the facts and is willing to
follow them, Agassiz sees the conflicts and fights them. Thus is the theme of
the first part of the book.

The second part moves to Concord and the collection of
Transcendentalists. This virtually self-contained community of mid-nineteenth
century thinkers see Darwin as a window onto their world. What would have been
seen as a putative conflict is seen for example in Thoreau's eyes as an
explanation for the natural harmony of his world of nature. It explains why a
small pine tree has managed to survive and prosper far from its source, and how
the squirrels take part in the dissemination of species who survive and the
fact that one sees robins and not parakeets in the Spring and pine trees and
not palm trees in the forests. At least that is what we are led to understand.

Somehow we get John Brown and his assault on Harper's Ferry
in the mix. One nexus is that Brown's two daughters end up at the Alcott's and
attend Concord Academy. This perhaps is the mixing of the abolitionist with the
evolutionist. One can see these individuals seeing in evolution, man from a
common ancestor, being the key element in their strong abolitionist views.
Namely the issue that all humans are from the same stock and thus have the same
rights. Not quite an acceptance of fundamental individualism, the belief that
all individuals have individual rights equally, but a step in that direction.

Now as to some specific observations:

p. 74 the comment on Thoreau adopting methods of science
without a scientific theory is an excellent observation. Thoreau was an
excellent observer of facts, but his core beliefs were more Transcendental than
scientific.

p 85 is an excellent introduction to Agassiz and his
grandiosity. One can even today on Oxford Street see this collection of the
naturalist age. This museum was to Agassiz what the American Museum of Natural
History and stuffed mammals was to Teddy Roosevelt. Namely an expression of what
they felt Nature was.

p 88 is a concise description of the view of Agassiz and his
dispute with the monogenesis view of a single human ancestor. Agassiz was of
the view that the "races" came from differing ancestors and as such
were different species.

pp. 108-109 This is a good discussion of Gray and his
negation of the Transcendental view. What is especially insightful is
understanding that induction was a key element of science. One collected facts
and then using a scientific method, Baconian in nature, assembled the facts and
from them induced a conclusion. That in essence was the heart of Darwin.

p. 111 This is a set of comments from Agassiz. Here he
states there can be no connection between an arctic whale and a tropical tiger.
This is done without basis. Had Agassiz understood DNA, a Century in the
coming, then the evidence would be there. This is a classic example of those
who prognosticate conclusions without the slightest evidence in facts.
Induction is always subject to some missteps, but ex cathedra statements are
often subject to near immediate disproof.

p. 141 This is an attempt to connect Darwin and Thoreau in
his Walden. It is not clear how accurate this may be. Thoreau as a believer in
nature qua nature had to see Nature as a temporal dynamic combative process.
Some elements of this may be culled from Walden but I suspect it may require a
deeper digging to fully justify.

p. 151 Here he states that Alcott invented Darwin's
evolutionary ideas. But this theory had creatures descending from man rather
than man from species. Perhaps this may have been stated differently.

p.247. The author states Thoreau died from influenza gotten
from Alcott. It appears that the generally accepted cause was TB from which
Thoreau had suffered for almost a decade. Perhaps a fact checking would work
here.

In summary, other than the title and some comments above,
the book is well written and well-structured for its purpose. It is not a
discussion of Darwin. Somehow one should come to the book with a good understanding
of Darwin circa 1860. That is missing. It is not a discussion of Darwin in
America, at best as noted just in Concord and Cambridge. Transcendentalism was
not a universally accepted view of the world at the time, in fact it was viewed
by many as idiosyncratic to that small portion of the Commonwealth.

Thursday, February 16, 2017

We thought Google Fiber was a dumb idea from the outset. Why? Well we tried it before they did. What was the problem. Costs. What costs. Three types. 1. Delay. It takes forever to get permits etc. The Incumbent can throw tons of stiff at you. 2. Franchise. You need one for every town. 3. Pole Attachments: Again the Incumbent. Fundamentally fiber can be real cheap. It costs about $20,000 per mile if nothing else is counted. Then if you consider the number of homes per mile at 50% penetration you can get the fiber down to $500 per customer! Drops are $200 and electronics per sub is about $300. Overall about $1,000. Then add the above and it goes to well over $3,000 and drop penetration to 25% and it doubles to $6,000! Now it is no longer a business. I recall speaking to some Google folks a decade or so ago. Back of the envelope stuff. It took them a decade and hundreds of millions to learn! That's Silicon Valley!

Eventually Google Fiber could offer even more radical wireless technologies. For example, Webpass has tested technology from Artemis Networks,
a startup building a new type of wireless service that can “follow”
users from place to place and guarantee a certain amount of bandwidth.
Developing those sorts of technologies is a radical departure from
building a network that provides actual fiber to homes, and requires a
different type of workforce. In a letter to employees about the
transition, Alphabet CEO Larry Page said the leaner Access will largely
work in the field, not from the company’s headquarters in Mountain View. A more wireless future for Fiber still comes with risks. More
traditional telcos are also eyeing high-speed wireless internet as a way
to bypass more expensive traditional broadband. In the meantime,
Alphabet is still trying to figure out how to be a company that provides
internet at all.

All you had to do was read what I wrote a decade or more ago. But that is West Coast vs East Coast. Wireless is the future, if one can get out of their own way. Now come Verizon. Buy Yahoo. Yeah, right. Look at Verizon stock, down almost 20% while the market is up 20%. Is the Board asleep? They are sitting on a gold mine in wireless licenses and they go after AoL and Yahoo. They could be the next Google in doing dumb things!

Monday, February 13, 2017

Let's say you have Leukemia. You are dying. Yep, near death. These bright folks have the solution. A thousand years ago they would have bled you, but now, they tax you! Yep. They tax you say $50,000, but, if you get well, well they give you a tax credit! Yep a good old Republican tax credit. That means if you live and get back out there in the fields cutting the sugar cane for 16 hours a day, you will not have to pay taxes for at least 50 years. If you die, then they get to put a lien on your estate, on top of the death tax, and the estate tax, and....

Don't we all love these Tax and Spend Republicans. Imagine what they can do replacing the ACA. Bad to worse? No way, think of all those tax credits you get if you somehow heal thyself!

After all, if it works for one kind of carbon why not another? Harvard can just shut down the Med School, and triple the Economics Department. And don't forget those folks at MIT who brought you the ACA in the first place! And they thought you were just dumb!

Thursday, February 9, 2017

Prostate cancer, PCa, is a significant cancer especially in
older men. It is more than likely a highly heterogeneous cancer and thus unlike
many of the others we have examined there may not be a single strategy. There
has been a significant amount of effort to try and determine if immunotherapy
can be applied to PCa. This is especially true in that it does metastasize to
the bone and many hematological cancers have been addressed by immunotherapy.
We have examined many details of PCa elsewhere and refer the reader to that[1].

As Drake, has indicated:

Prostate cancer is not traditionally considered an
immunologically responsive malignancy like melanoma or renal cell carcinoma,
yet the prostate glands of men with cancer are frequently diffusely infiltrated
with both CD4 and CD8 T cells, and several factors suggest that adenocarcinoma
of the prostate might prove an attractive target for immunotherapy.

First among these is the slow-growing nature of the
disease, allowing time for immunological intervention to overcome immunosuppressive
factors1 in the tumor microenvironment and to mount a clinically meaningful
response.

Second, serum PSA level, while not a true surrogate
marker, is routinely utilized in clinical decision making, and can serve to
guide the development of immunotherapy approaches.

Third, both proteomic and microarray analyses of prostate
cancer progression have delineated a number of relatively tissue-specific
proteins that may serve as tumor/tissue antigens.

Finally, abundant preclinical data suggest that an
antitumor immune response can be elicited, particularly when active
immunotherapy is combined with maneuvers to mitigate tolerance such as immune
checkpoint blockade, androgen ablation, or radiotherapy.

At least five phase III immunotherapy trials have been
initiated in the context of metastatic, castrate-resistant prostate cancer, but
none have yet met their predetermined end points

PCa has had a limited success with immunotherapy but not as
successful as other cancers. We will argue that a main reason is the complex
genetic makeup of PCa. However, the current genetic/immunological tool box
available may offer some new options.

The Prostate

The prostate is a glandular organ which appears upon
microscopic examination as a multiplicity of glands with muscle, nerve, blood, and
other stromal and parenchymal tissues. It has a high incidence of cancer as men
age and the cancers for the most part are indolent, namely have low chance of
metastasis, yet a fraction show highly aggressive behavior. Also an alleged
precursor of PCa, prostate cancer, is High Grade Prostate Intraepithelial
Neoplasia, an inflammatory disorder wherein the existing glandular regions
generally composed of basal and luminal cells, demonstrate significant growth
within the gland itself. It has been argued that this is a natural precursor to
PCa but we have demonstrated that the conclusion has significant exceptions.
Yet we know that inflammation is a driver to cancers and there thus is a
putative correlation but not a causation. (See Nunzio et al):

Evidence in the peer-reviewed literature suggested that
chronic prostatic inflammation may be involved in the development and
progression of chronic prostatic disease, such as BPH and PCa, although there
is still no evidence of a causal relation. Inflammation should be considered a
new domain in basic and clinical research in patients with BPH and PCa.

PCa is quite complex on a genetic basis. Berger et al have
discussed this at length. They state:

Prostate cancer is the second most common cause of male
cancer deaths in the United States. Here we present the complete sequence of
seven primary prostate cancers and their paired normal counterparts. Several
tumors contained complex chains of balanced rearrangements that occurred within
or adjacent to known cancer genes.

Rearrangement breakpoints were enriched near open
chromatin, androgen receptor and ERG DNA binding sites in the setting of the
ETS gene fusion TMPRSS2-ERG, but inversely correlated with these regions in
tumors lacking ETS fusions. This observation suggests a link between chromatin
or transcriptional regulation and the genesis of genomic aberrations. Three
tumors contained rearrangements that disrupted CADM2, and four harbored events
disrupting either PTEN (unbalanced events), a prostate tumor suppressor, or
MAGI2 (balanced events), a PTEN interacting protein not previously implicated
in prostate tumorigenesis. Thus, genomic rearrangements may arise from
transcriptional or chromatin aberrancies to engage prostate tumorigenic
mechanisms.

We have further examined this in detail in McGarty, Prostate
Cancer (2012). Now in 2009 Drake stated:

Prostate cancer is not traditionally considered an
immunologically responsive malignancy like melanoma or renal cell carcinoma,
yet the prostate glands of men with cancer are frequently diffusely infiltrated
with both CD4 and CD8 T cells, and several factors suggest that adenocarcinoma
of the prostate might prove an attractive target for immunotherapy.

First among these
is the slow-growing nature of the disease, allowing time for immunological
intervention to overcome immunosuppressive factors in the tumor
microenvironment and to mount a clinically meaningful response.

Second, serum PSA level, while not a true surrogate
marker, is routinely utilized in clinical decision making, and can serve to
guide the development of immunotherapy approaches.

Third, both proteomic and microarray analyses of prostate
cancer progression have delineated a number of relatively tissue-specific
proteins that may serve as tumor/tissue antigens.

Finally, abundant preclinical data suggest that an
antitumor immune response can be elicited, particularly when active
immunotherapy is combined with maneuvers to mitigate tolerance such as immune
checkpoint blockade, androgen ablation, or radiotherapy.

At least five phase III immunotherapy trials have been
initiated in the context of metastatic, castrate-resistant prostate cancer, but
none have yet met their predetermined end points

Drake was noting the potential for immunotherapeutic approaches
for this solid tumor. It is well known that the prostate is subject to various
inflammatory factors and that these factors have been linked to cancer changes.
The counter would be to examine using the immune responses to address the
changes. As we noted in melanoma, when observed, a melanoma often has an
accumulation of T cells, CTLs, indicating the natural defense mechanism.

On the other hand, it is intriguing to note the significant
impact that inflammation has on PCa and that immune response are present but
not yet active.

Current Techniques; Dendritic

One of the earliest treatments of PCa using an
immunotherapeutic approach is to use the patient's dendritic cells and prime
them. Recall that the dendritic cells are out in the body searching for
intruders. When they find one they then bring it back to the immune system for
presenting and for activating the immune system. Thus, rather than modifying a
T cell or an NK cell directly, the approach seeks to "prime" the
dendritic cells which will then start the immune response. This is an example
of examining the many entry points into using the immune system.

As Westdorp et al note:

Prostate cancer (PCa) is the most common cancer in men
and the second most common cause of cancer-related death in men. In recent
years, novel therapeutic options for PCa have been developed and studied
extensively in clinical trials. Sipuleucel-T is the first cell-based
immunotherapeutic vaccine for treatment of cancer. This vaccine consists of
autologous mononuclear cells stimulated and loaded with an immunostimulatory
fusion protein containing the prostate tumor antigen prostate acid posphatase.

The choice of antigen might be key for the efficiency of
cell-based immunotherapy. Depending on the treatment strategy, target antigens
should be immunogenic, abundantly expressed by tumor cells, and preferably
functionally important for the tumor to prevent loss of antigen expression.
Autoimmune responses have been reported against several antigens expressed in
the prostate, indicating that PCa is a suitable target for immunotherapy.

In this review, we will discuss PCa antigens that exhibit
immunogenic features and/or have been targeted in immunotherapeutic settings
with promising results, and we highlight the hurdles and opportunities for
cancer immunotherapy.

The authors above then consider a collection of putative
prostate antigens useful for applications of multiple approaches.

Antigen

Function

Action

PSA

PSA Serine
protease which cleaves high molecular weight proteins into smaller peptides,
resulting in the necessary liquification for spermatozoa to swim freely

Now for the dendritic cell targets they employ PAP as above
as well as GM-CSF. The dendritic cells mature in a solution with a fusion
protein (PA2024). The result is returned to the patient.

As Drake noted in 2009:

One of the few immunotherapy agents in late-stage
development for prostate cancer is Sipuleucel-T. In this approach, patients
undergo plasmapheresis, and a personalized immunotherapy product is produced by
culturing a patient’s peripheral blood monocytes with a proprietary protein
that couples granulocyte macrophage colony-stimulating factor with a target
antigen (PAP).

Phase I and phase III trials of Sipuleucel-T have been
reported, with encouraging results. Clinical development of this agent is pivotal
on a large (500 patients) randomized placebo-controlled phase III trial
(ImPACT; Immunotherapy Prostate Adenocarcinoma Treatment) which completed
accrual in October 2007, and for which additional survival data are expected
sometime this year (see Note Added in Proof).

In addition, considerable clinical development has
focused on a viral vector approach in which PSA itself is targeted using
sequential injections with recombinant vaccinia and fowlpox constructs. Here,
both constructs have been engineered to include a number of costimulatory
molecules in an effort to augment an immune response.

As Jahnisch et al note:

Dendritic cells (DCs) are professional antigen-presenting
cells (APCs), which display a unique capacity to induce, sustain, and regulate
T-cell responses. In tumor setting, DCs circulate through the blood and migrate
to tumor tissues, where they interact with malignant cells. Immature DCs are
particularly efficient in the uptake of tumorderived material. DC maturation is
induced by tumorderived molecules such as heat shock proteins and high mobility-
group box 1 protein as well as proinflammatory cytokines produced by various
tumor-infiltrating immune cells.

Clinical studies focusing on the adoptive transfer of
cytotoxic effector cells revealed tumor regression in cancer patients. CD4+ T
cells recognizing peptides in the context of HLA class II molecules also play
an important role in antitumor immunity. CD4+ T cells improve the capacity of
DCs to induce CTLs by the interaction between CD40 on DCs and CD40 ligand on
activated CD4+ T cells.

In addition, CD4+ T cells provide help for the
maintenance and expansion of CTLs by secreting cytokines such as interleukin
(IL)-2 and can eradicate tumor cells directly. Besides their extraordinary
capacity to induce and stimulate T-cell responses, DCs efficiently improve the
immunomodulatory and cytotoxic potential of natural killer cells, which
essentially contribute to the elimination of tumor cells.

Furthermore, DCs can also directly mediate tumor-directed
cytotoxicity. Owing to their various antitumor effects, DCs evolved as
promising candidates for vaccination protocols in cancer therapy

Now as Mellman et al note:

While Provenge is clearly a cell-based therapy, there may
be other mechanisms involved. Although the majority (66%) of survivors showed
an antibody response to the fusion protein, the fraction of patients producing
antibodies that recognized endogenous PAP was much lower (28.5%).

Moreover, T-cell responses to either the fusion protein
or PAP were not associated with survival. These discrepancies might reflect a
limitation of monitoring antitumor immune responses in the peripheral blood
compared with the tumour microenvironment. However, they also raise the
possibility that other undefined factors in the cellular product may have an
important role. Further studies are required to understand the therapeutic
mechanism of Provenge, and to define the impact of the different
cell-processing procedures on the placebo product. The lack of tumour
shrinkage, the criterion typically used to gauge the efficacy of cancer
treatments, in the face of a survival benefit is surprising, but perhaps not
unexpected for immunotherapy. As seen pre-clinically, an effect on pre-existing
tumour due to immune manipulations can be delayed while an immune response
develops.

Furthermore, biopsies of metastases after vaccination in
some clinical trials revealed the presence of immune infiltrates that mediate
tumour destruction in association with extensive edema, which may be followed
by fibrosis46.

These histopathological findings suggest that monitoring
tumour size alone may be inadequate for assessing the overall therapeutic effects
of vaccination. As discussed later, these considerations apply to the
evaluation of CTLA-4 antibody blockade, highlighting the need to modify tumour
response criteria in light of new insights into the biology of immunotherapy.

Now Mellman et al make several key points as to the
dendritic approach. First, RESIST approaches measure tumor size and in classic
chemotherapy cases it does shrink. Yet as has been seen again and again in the
more sophisticated and targeted approaches the shrinking takes time as the
tumor, albeit present, it being attacked and killed off, albeit still visible
on say a CAT Scan. Second, there is the putative supposition that there are
other factors afoot. The latter we shall explore with the checkpoint
examination.

Checkpoint Targets

Checkpoints are simply receptor-ligand pairs which when
activated can inhibit the actions of T cells and other immune pathway actions.
As Topalian et al note:

The rapid-fire clinical successes from blocking CTLA-4
and PD-1, the first checkpoint receptors to be discovered, have opened prospects
for extending the potential of cancer immunotherapy by inhibiting more recently
discovered checkpoint ligands and receptors. It is clear that, despite some
commonalities, CTLA-4 and PD-1 have distinct patterns of expression, signaling
pathways, and mechanisms of action. Although discovered over 20 years ago,
there are still many unanswered questions about their biology, particularly in
the context of cancer.

The authors continue:

The immune system recognizes and is poised to eliminate
cancer but is held in check by inhibitory receptors and ligands. These immune
checkpoint pathways, which normally maintain self-tolerance and limit
collateral tissue damage during anti-microbial immune responses, can be
co-opted by cancer to evade immune destruction. Drugs interrupting immune
checkpoints, such as anti-CTLA-4, anti-PD-1, anti-PD-L1, and others in early
development, can unleash anti-tumor immunity and mediate durable cancer
regressions. The complex biology of immune checkpoint pathways still contains
many mysteries, and the full activity spectrum of checkpoint-blocking drugs,
used alone or in combination, is currently the subject of intense study.

Thus, the issue would be; what other check points are there
and how can they be addressed? From Kono we have the following Table which
presents some putative targets:

Ipilimumab is a fully human monoclonal immunoglobulin G1
antibody that increases antitumor T-cell responses by binding to cytotoxic
T-lymphocyte antigen 4.17-19 Blocking by ipilimumab of the T-cell negative
regulator cytotoxic T-lymphocyte antigen 4 allows CD28 and B7 interactions,
which result in T-cell activation; proliferation; tumor infiltration; and
ultimately, cancer cell death. Treatment with ipilimumab, as a single agent or
in combination with dacarbazine, provided significant survival benefit in two
phase III trials of advanced melanoma. Of note, approximately 20% of
ipilimumab-treated patients with melanoma experienced longterm survival

We have seen this in detail when examining the melanoma
therapeutic approaches. Now the application of this to PCa is interesting and
challenging. Melanoma is an aggressive and rapidly growing cancer and it is
well known that it often evokes an immune response when examined on biopsy. In
contrast PCa is quite different. Melanoma is derived from melanocytes which have
developed from the neural crest. PCa is exocrine glandular. The results of the
Beer trial were not conclusive.

More recently Schweizer and Drake (2014) noted:

Since the approval of sipuleucel-T for men with
metastatic castrate resistant prostate cancer in 2010, great strides in the
development of anti-cancer immunotherapies have been made. Current drug
development in this area has focused primarily on antigen specific [i.e. cancer
vaccines and antibody based therapies)] or checkpoint inhibitor therapies, with
the checkpoint inhibitors perhaps gaining the most attention as of late.

Indeed, drugs blocking the inhibitory signal generated by
the engagement of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell
death-1 (PD-1) found on T-cells has emerged as potent means to combat the immunosuppressive
milieu. The anti-CTLA-4 monoclonal antibody ipilimumab has already been approved
in advanced melanoma and two phase III trials evaluating ipilimumab in men with
metastatic castrate-resistant prostate cancer are underway.

A phase III trial evaluating ProstVac- VF, a
poxvirus-based therapeutic prostate cancer vaccine, is also underway. While
there has been reason for encouragement over the past few years, many questions
regarding the use of immunotherapies remain.

Namely it is unclear what stage of disease is most likely
to benefit from these approaches, how best to incorporate said treatments with
each other and into our current treatment regimens and which therapy is most
appropriate for which disease. Herein we review some of the recent advances in
immunotherapy as related to the treatment of prostate cancer and outline some
of the challenges that lie ahead.

More recently Martin et al noted:

Primary prostate cancers are infiltrated with PD-1
expressing CD8+ T cells. However, in early clinical trials, men with mCRPC did
not respond to PD-1 blockade as a monotherapy. One explanation for this
unresponsiveness could be that prostate tumors generally do not express PD-L1,
the primary ligand for PD-1.

However, lack of PD-L1 expression in prostate cancer
would be surprising, given that PTEN loss is relatively common in prostate
cancer and several studies have shown that PTEN loss correlates with PD-L1
up-regulation - constituting a mechanism of innate immune resistance. This
study tested whether prostate cancer cells were capable of expressing PD-L1,
and whether the rare PD-L1 expression that occurs in human specimen's
correlates with PTEN loss…These studies show that some prostate cancer cell
lines are capable of expressing PD-L1.

However, in human prostate cancer, PTEN loss is not
associated with PD-L1 expression, arguing against innate immune resistance as a
mechanism that mitigates anti-tumor immune responses in this disease.

Unfortunately, the results are less than positive. They seem
to agree with the prior results.

Options

There are many options available for dealing with PCa but
the efficacy of these known options is at best problematic. Yoo et al have
summarized the recent (2016) immunotherapeutic options for PCa. They note the
following:

Despite advances in treatment of prostate cancer,
curative therapy is not yet available for CRPC. Novel therapeutic options have
thus been sought, and vaccines, immunotherapy, and gene based therapy are
considered to be attractive candidates in this respect.

Up to now, sipuleucel-T is the only such treatment
approved by the Food and Drug Administration.

GX301is a dual-adjuvant telomerase vaccine. GX301 is
reported to be safe and highly immunogenic in patients with prostate cancer. A
Phase II randomized trial is underway.

Prostvac is a vector based therapeutic cancer vaccine. A
Phase II study reported that prostvac was well tolerated and it improved
overall survival compared with control vectors (25.1 months vs. 16.6 months) in
patients with minimally symptomatic CRPC. However, another Phase II study,
which evaluated the effect of the combination of docetaxel and prostvac, failed
to show improvements in overall survival; this lack of positive results may be
due to limited accrual of patients. Investigation on the relative efficacy of
simultaneous versus sequential docetaxel þ prostvac is currently ongoing.

DCVAC is an autologous dendritic cell-based vaccine. In a
Phase I and II trial, combination chemoimmunotherapy with DCVAC and docetaxel
resulted in longer than expected survival (19 months vs. 11.8 months) without
significant complications. A Phase III study, evaluating the merits of DCVAC
when added to standard chemotherapy, is due to commence.

Vaccines have been examined by many over the past few years.
As noted, perhaps multi-therapeutic methods may also prove beneficial.

5.2. Immunotherapy

Ipilimumab[2]
is a monoclonal antibody that blocks the activity of CTLA-4 (cytotoxic
T-lymphocyte-associated protein 4) and was approved by the Food and Drug
Administration for the treatment of melanoma in 2011. As preclinical and
clinical studies suggested that radiotherapy might activate the immune system
in patients with prostate cancer, a Phase III trial of ipilimumab in addition
to radiotherapy for metastatic CRPC patients was initiated. However, this Phase
III study did not show any improvement in overall survival after radiotherapy
followed by ipilimumab, compared with radiotherapy followed by placebo.

Currently, combination trials with abiraterone, ADT,
sipuleucel-T, and prostvac are underway. 177Lu-J591, a humanized monoclonal
antibody, was primarily developed in a radiolabeled form for PET, binding to
the extracellular domain of prostate-specific membrane antigen (PSMA). After
binding to PSMA, the 177Lu-J591ePSMA complex undergoes endocytosis and is
accumulated in prostate cancer cells.

In this regard, 177Lu-J591J591 is considered to be a
potential carrier for cytotoxic drug conjugates to maximize therapeutic
effectiveness and a promising agent for radioimmunotherapy. Currently, a Phase
2 clinical trial is in the process of patient recruitment.

Immunotherapy via check point inhibitors has become quite
popular after the success in melanoma therapy. It has not, however, seen as
significant in PCa.

5.3. Gene-based therapy

Olaparib, recently approved for treating ovarian cancer
with BRCA1/2 mutations, is a poly-ADT-ribose polymerase inhibitor.
Poly-ADT-ribose polymerase is involved in the DNA repair process, and genomic
aberrations observed in CRPC are thought to confer sensitivity to
poly-ADTribose polymerase inhibitors. In recent studies, olaparib showed a
considerable response rate of 33% in post-docetaxel prostate cancer patients
with defects in DNA repair genes, and a Phase II trial has commenced.

Thus, the only accepted approach is the dendritic approach
that have been approved. The checkpoint approach has not yield any significant
positive result although trial continue.

Let us review the options.

Let us examine these in some further detail in the following
Table. In this Table, we lay out some options for consideration.

Approach

Mode of Operation

Issues/Opportunities

Dendritic

The dendritic cells are antigen
presenting cells. They manage to move throughout the body and identify
various potential pathogens.

This seems to be the first of the
putatively efficacious approaches in dealing with PCa.

CTL

Cytotoxic T Lymphocytes, Killer T cells, are the T cells
which are an integral part of the adaptive immune system.

CTL need targeting via Ab specific paths.

NK

NK cells are part of the innate
immune system, albeit being a lymphocyte lineage. They function by a
balancing act between activators and inhibitors.

NK cells are effective innate
killers of intruders. However, they can also release their killing cytokines
which in turn may do harm to cells.

Mab

Monoclonal antibodies, Mab, are fundamentally Ab designed
to recognize certain antigens, or epitopes, and attach to them and bring out
the adaptive immune system response.

Mabs require the identification of targets. These targets
must have some uniqueness.

CRISPR

CRISPRs allow for the editing of
genes for the inclusion or excision of segments of DNA.

CRISPRs are somewhat independent
of targets per se. They may have the ability to find alternative means for
attacking the PCa cells.

CAR T

CAR T cells are T cells which have been genetically
modified to attack specific targets which would normally be suppressed by MHC
surface molecules identifying the cell as self.

Gene Drives have been used in trying
to "drive" a specific gene into some species. They generally drive
at the embryo level, the fundamental stem cell level is you will, into a species.
However, one could consider this also being used to "drive" into T
cells or NK cells the ability to attack specific PCa cells.

Gene Drives can potentially drive
into the stem cells of the immune system. Instead of changing the total
species they can introduce self-replicating cells to attack the PCa.

CIK cells have shown to be effective is properly targeted.
They have not been so for PCa but perhaps their broader spectrum capability
for genetic markers may be useful.

Observations

Based upon some of the recent results there are several observations
worth examining. The most significant issue is the complexity of the PCa
genome. Thus, the main problem we believe in PCa is the complex nature of the
genetic makeup. As Gundem et al noted in 2015:

Cancers emerge from an ongoing Darwinian evolutionary
process, often leading to multiple competing sub-clones within a single primary
tumour. This evolutionary process culminates in the formation of metastases, which
is the cause of 90%of cancer-related deaths. However, despite its clinical
importance, little is known about the principles governing the dissemination of
cancer cells to distant organs. Although the hypothesis that each metastasis
originates from a single tumour cell is generally supported, recent studies
using mouse models of cancer demonstrated the existence of polyclonal seeding
from and inter-clonal cooperation between multiple sub-clones.

Here we sought definitive evidence for the existence of polyclonal
seeding in human malignancy and to establish the clonal relationship among
different metastases in the context of androgen deprived metastatic prostate
cancer. Using whole-genome sequencing, we characterized multiple metastases
arising from prostate tumour in ten patients. Integrated analyses of sub-clonal
architecture revealed the patterns of metastatic spread in unprecedented detail.
Metastasis-to-metastasis spread was found to be common, either through de novo
monoclonal seeding of daughter metastases or, in five cases, through the
transfer of multiple tumour clones between metastatic sites.

Lesions affecting tumour suppressor genes usually occur
as single events, whereas mutations in genes involved in androgen receptor
signalling commonly involve multiple, convergent events in different metastases.
Our results elucidate in detail the complex patterns of metastatic spread and
further our understanding of the development of resistance to
androgen-deprivation therapy in prostate cancer.

Namely many genetic changes are occurring continuously as
PCa progresses. Thus, seeking a single marker may be fruitless. Yet, the immune
approach can be designed to address the significant genetic complexity of PCa.
Namely by addressing a broad spectrum of possible cells as would be the case
with a CIK approach one could envision a treatment akin to a chronic disorder.

About Me

Terry has spent most of his career in industry, half in corporate executive positions, and half involved in his start ups. He started on the Faculty and Staff at MIT in 1967 and was there until 1975, and he had returned to MIT from 2005 to 2012 to assist groups of doctoral and post doc students. Terry has focused on a broad set of industries from cable, to satellite, wireless, and even health care software and medical imaging. Terry has published extensively in a broad set of areas as well as having written several books. Terry's view is that of an entrepreneur who has built companies in over twenty countries.
Copyright 2008-2015 Terrence P McGarty all rights reserved.
NOTE: This blog contains personal opinions of the author and is not meant in any manner to provide professional advice, medical advice, financial advice. Reliance on any of the opinions contained herein is done at the risk of the user.

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